Targeting Annexin II Function with Small Molecule Natural Products as a Novel Anti-Cancer Strategy

Persistent Link:
http://hdl.handle.net/10150/195752
Title:
Targeting Annexin II Function with Small Molecule Natural Products as a Novel Anti-Cancer Strategy
Author:
Falsey, Ryan Richard
Issue Date:
2006
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
The establishment and dissemination of cancers is dependent not only on the dysregulation of cell autonomous processes, but also on the ability of tumor cells to establish an adequate blood supply in their host environment (neoangiogenesis) and escape local tissue constraints (metastasis). The key proteins that mediate each of these processes are highly sought after as potential therapeutic targets. Annexin AII (AII) is a cellular protein that plays a critical role in multiple cancer relevant processes such as metastasis, angiogenesis, and mitogenic signal transduction. Studies have correlated elevated levels of AII with aggressive tumors. However, the multiple roles of AII have made it difficult to define specific mechanisms by which the protein can contribute to a malignant phenotype. Using a cell-based reporter assay, we have identified Withaferin A (WA) from Withania somnifera, a plant with medicinal uses that date back to over 3,000 years in Ayurvedic medicine, as a small molecule natural product that interacts with the AII protein. Work in our laboratory has shown that WA disrupts F-actin organization via a covalent interaction with AII that results in concentration-dependent cytotoxicity and marked anti-invasive activity in tumor cells. We also determined the effects of WA on AII-dependent endothelial cell plasmin generation and network formation. In vivo mouse xenograft models utilizing WA against Ewing's sarcoma were performed to further characterize the anti-tumor activity of WA. Our findings indicate that WA is a potent anti-tumor agent, resulting in decreased endothelial cell plasmin generation, tumor growth inhibition and reduced blood vessel formation both in vitro and in vivo.The potent anti-tumor activity of WA suggests that AII represents a previously unexploited target for therapeutic intervention by small molecule drugs. Our in vitro findings and animal studies indicate that WA therapy has potent anti-tumor effects and supports the notion of WA serving as lead for the synthesis of new compounds that target AII function. Furthermore, as a small molecule modulator of AII function, WA provides a tool to study the complex cellular functions of AII.
Type:
text; Electronic Dissertation
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Cancer Biology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Whitesell, Luke
Committee Chair:
Whitesell, Luke

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleTargeting Annexin II Function with Small Molecule Natural Products as a Novel Anti-Cancer Strategyen_US
dc.creatorFalsey, Ryan Richarden_US
dc.contributor.authorFalsey, Ryan Richarden_US
dc.date.issued2006en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractThe establishment and dissemination of cancers is dependent not only on the dysregulation of cell autonomous processes, but also on the ability of tumor cells to establish an adequate blood supply in their host environment (neoangiogenesis) and escape local tissue constraints (metastasis). The key proteins that mediate each of these processes are highly sought after as potential therapeutic targets. Annexin AII (AII) is a cellular protein that plays a critical role in multiple cancer relevant processes such as metastasis, angiogenesis, and mitogenic signal transduction. Studies have correlated elevated levels of AII with aggressive tumors. However, the multiple roles of AII have made it difficult to define specific mechanisms by which the protein can contribute to a malignant phenotype. Using a cell-based reporter assay, we have identified Withaferin A (WA) from Withania somnifera, a plant with medicinal uses that date back to over 3,000 years in Ayurvedic medicine, as a small molecule natural product that interacts with the AII protein. Work in our laboratory has shown that WA disrupts F-actin organization via a covalent interaction with AII that results in concentration-dependent cytotoxicity and marked anti-invasive activity in tumor cells. We also determined the effects of WA on AII-dependent endothelial cell plasmin generation and network formation. In vivo mouse xenograft models utilizing WA against Ewing's sarcoma were performed to further characterize the anti-tumor activity of WA. Our findings indicate that WA is a potent anti-tumor agent, resulting in decreased endothelial cell plasmin generation, tumor growth inhibition and reduced blood vessel formation both in vitro and in vivo.The potent anti-tumor activity of WA suggests that AII represents a previously unexploited target for therapeutic intervention by small molecule drugs. Our in vitro findings and animal studies indicate that WA therapy has potent anti-tumor effects and supports the notion of WA serving as lead for the synthesis of new compounds that target AII function. Furthermore, as a small molecule modulator of AII function, WA provides a tool to study the complex cellular functions of AII.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineCancer Biologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorWhitesell, Lukeen_US
dc.contributor.chairWhitesell, Lukeen_US
dc.contributor.committeememberGunatilaka, Leslieen_US
dc.contributor.committeememberMahadevan, Darukaen_US
dc.contributor.committeememberBowden, G. Timen_US
dc.contributor.committeememberNagle, Raymonden_US
dc.identifier.proquest1862en_US
dc.identifier.oclc659747321en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.